The Vancouver Grizzlies applied with the NBA to relocate to Memphis on March 26, 2001 and it was granted. As a result, the Grizzlies became the first major professional sports team from the "big four" major pro sports leagues to permanently play its home games in Memphis, as well as leaving the Toronto Raptors to be the only Canadian basketball team in the NBA. Memphis became the easternmost city in the Western Conference. In their first three seasons in Memphis, the Grizzlies played their home games at the Pyramid Arena.

Brown won the NBA Coach of the Year Award during the next season when the Grizzlies made the NBA playoffs for the first time in team history in 2004 as the sixth seed in the Western Conference in a drastic change from being perennially one of the worst teams in the NBA. They also won a then record 50 games under Gasol and Williams. In the playoffs they faced the San Antonio Spurs, who swept them out of the playoffs in four games.

Brown stepped down as head coach during the 2004–05 NBA season. At the time of his resignation, the Grizzlies had a losing record but West hired TNT analyst and former coach Mike Fratello to replace Brown. The Grizzlies' record improved and the team advanced to the postseason for the second consecutive season. However, the Grizzlies were swept out in the first round again, this time by the Phoenix Suns. After the season, which ended with anger between Fratello and many of the players, namely Bonzi Wells and Jason Williams, the team had an active 2005 off-season in which they revamped the team and added veterans. While the Grizzlies lost Wells, Williams, Stromile Swift, and James Posey, they acquired Damon Stoudamire, Bobby Jackson, Hakim Warrick, and Eddie Jones. They made the playoffs for the third consecutive year as well.

With their record they had the fifth seed in the Western Conference playoffs and would face the Dallas Mavericks, who swept the Grizzlies in 4 games.

Following the 2006 NBA draft, Jerry West traded Shane Battier to the Houston Rockets for their first round pick Rudy Gay and Stromile Swift. Before the 2006–07 season, they suffered a blow when Gasol broke his left foot while playing for Spain in the World Championships. The Grizzlies started the season 5–17 without Gasol, and then went 1–7 while he was limited to about 25 minutes per game. At that point, Fratello was fired and replaced by Tony Barone, Sr. as interim coach. Barone was the team's player personnel director and had never coached an NBA game though he had coached at the collegiate level for both Creighton and Texas A&M being named coach of the year in their conferences three times during his tenure.

The Grizzlies finished the 2006–07 season with a league-worst 22–60 record, and Jerry West announced his resignation from his position as the team's general manager shortly after the end of the regular season. The team also hired Marc Iavaroni, who was previously with the Phoenix Suns as an assistant coach, to be the team's new head coach. Despite the last-place finish, the Grizzlies, who held the best chance of landing the first pick, ended up with the fourth pick in the 2007 NBA draft, with which the Grizzlies selected Mike Conley, Jr.

On January 22, 2009, head coach Marc Iavaroni was fired and replaced on an interim basis by assistant coach Johnny Davis for two games. Lionel Hollins was named the Grizzlies' permanent head coach on January 25, 2009.[10]

On June 25, 2009, with the second overall pick in the NBA Draft, Memphis selected Hasheem Thabeet, then selected DeMarre Carroll with the 27th overall pick. On September 9, 2009, the Grizzlies signed free agent Allen Iverson to a one-year, $3.5 million deal. He only played three games (none in Memphis) before he left for "personal problems". He was then waived by the Grizzlies.[11][12] Following Iverson's departure, the Grizzlies improved. With new acquisition Zach Randolph playing at an All-Star level, Marc Gasol's improvement, and a commitment to defense, the Grizzlies were in playoff contention for much of the 2009–10 NBA season, before finishing 10th in the Western Conference with a win-loss record of 40–42.

Going into the 2010–11 season the Grizzlies celebrated the tenth year of basketball in Memphis. The season started with tremendous enthusiasm by the fan base in the Memphis area. Although the Grizzlies and their fans were celebrating the tenth season, the Grizzlies were also cheering for the 8th spot in the Western Conference Playoffs. They finished with a 46–36 record. The Grizzlies found their way back into the post-season for the first time in five years in the 2010–11 NBA season after a 101–96 home victory over the Sacramento Kings on April 8, 2011.[13] While in the playoff hunt in February 2011, the Grizzlies traded Hasheem Thabeet, DeMarre Carroll, and a protected future first-round pick to the Houston Rockets for Shane Battier, and Ishmael Smith.

The team became known locally and nationally for its "Grit and Grind"-style of basketball which means disruptive defense through high pressure on the ball (they were the team with the most steals per game in 2010–11) and their inside-out offense (they were the highest scoring team in the paint also). The Grizzlies achieved several firsts in franchise history during the 2011 NBA Playoffs. Entering the playoffs as an eighth seed, the team won their first playoff game in franchise history on April 17, 2011 with a 101–98 victory on the road against the top seeded San Antonio Spurs. Memphis then won their first home playoff game when they beat the Spurs 91–88 on April 23, 2011.[14] Finally, on April 29, the team won their first playoff series when they beat the Spurs in game 6, 99–91 to win the series 4 games to 2. This was only the fourth time in NBA history that an 8 seed defeated a 1 seed, and only the second time in a best-of-seven series (the first two were in a best-of-five series).[15] The Grizzlies' historic season came to an end after the Oklahoma City Thunder defeated them in game 7 of the Western Conference Semifinals.[16]

The Grizzlies found their way back into the post-season for the second time in six years in the 2011–12 NBA season after a 103–91 home victory over the New Orleans Hornets on April 18, 2012. They finished the 2011–12 season with a 41-25 record, 4th in the Western Conference. However, they were eliminated in the first round by the Los Angeles Clippers in seven games.

On June 11, 2012, Michael Heisley reportedly had an agreement in principle to sell the Memphis Grizzlies to communications technology magnate Robert J. Pera, who at 34 had a spot on Forbes' 2012 list of the 10 youngest billionaires in the world.[18] The purchase price was in the $350 million range. On August 23, 2012, Pera reached an agreement with a group of local partners including J.R. "Pitt" Hyde, Staley Cates, Ed Dobbs, Duncan Williams and Billy Orgel.[19][20] On October 25, 2012, Robert Pera was officially approved as the owner of the Memphis Grizzlies.[21][22] On November 4, 2012, Pera named Jason Levien the Chief Executive Officer and Managing Partner of the Memphis Grizzlies.[23] On December 13, 2012, ESPN announced that John Hollinger was hired by the Grizzlies as their new Vice President of Basketball Operations.

At the end of the season, Memphis finished with their best franchise record of 56-26, 2nd in the Division and as the 5th seed in the Playoffs. Also, Marc Gasol was NBA Defensive Player of the Year. In the opening round, Memphis defeated the Los Angeles Clippers in 6 Games after trailing in the series 0-2. This avenged their defeat from the previous year at the hands of the Clippers. Memphis then went on to the Western Conference Finals for the first time in franchise history when they defeated the Oklahoma City Thunder 4-1 in their semi-finals series. This was a rematch of their meeting in the 2011 NBA Playoffs, which the Thunder won in 7 games. However, the Grizzlies' season ended in the conference finals as they were swept by the eventual conference champions, San Antonio Spurs in yet another rematch/reversal from the 2011 NBA Playoffs.

The Grizzlies struggled to begin the 2013–14 season, starting out at 14-18 with Marc Gasol out, and entered the All-Star break with a win-loss record of 29-23. They went 21-9 after, finishing in 3rd place in the Southwest division and in 7th place in the Western Conference with a win-loss record of 50-32, including a 14-game winning streak at FedExForum. They faced the Oklahoma City Thunder in the playoffs and had a record four straight overtimes from games 2-5, going 3-1 in the overtimes. The Grizzlies fell 4-3, despite an effort by Gasol in game 7 without Zach Randolph after he was suspended for punching Thunder center Steven Adams in game 6.

On October 29, 2014, the Grizzlies defeated the Minnesota Timberwolves 105-101 for the franchise's first victory in a season opener since 2000, the year before the team moved to Memphis.[26] In the 2014–15 NBA season, the Grizzlies made the NBA playoffs as the 5th seed in the Western Conference. In the first round, the Grizzlies defeated the Portland Trail Blazers in five games. Games 4 and 5 were played without Mike Conley, who in Game 3 suffered multiple facial fractures in a collision with Blazers guard C. J. McCollum. In the second round, they found themselves facing off against the top seeded Golden State Warriors and MVP Stephen Curry. The Warriors took Game 1, and Conley returned in Game 2 to lead the Grizzlies to a 108-95 victory. Memphis took a 2-1 series lead before Golden State ultimately dispatched the Grizzlies in 6 games.

On April 1, 2016, the Grizzlies signed their 28th player for the season, an NBA record.[27]

The Grizzlies hold the draft rights to the following unsigned draft picks who have been playing outside the NBA. A drafted player, either an international draftee or a college draftee who isn't signed by the team that drafted him, is allowed to sign with any non-NBA teams. In this case, the team retains the player's draft rights in the NBA until one year after the player's contract with the non-NBA team ends.[28] This list includes draft rights that were acquired from trades with other teams.

Despite being one of the youngest squads in the NBA, the Grizzlies are rivals with the Los Angeles Clippers. The Grizzlies and Clippers have been rivals since the 2011–12 season, when the Clippers eliminated the Grizzlies in the first round of the 2012 NBA Playoffs 4 games to 3. The Grizzlies returned the favor in the 2012–13 season, eliminating the Clippers in the first round of the 2013 NBA Playoffs 4 games to 2. There have also been violent scuffles between the players, mainly between the Grizzlies Zach Randolph and the Clippers Blake Griffin. The Grizzlies are also the first team to draw an ejection on Clippers guard Chris Paul after he elbowed Marc Gasol in the ribs in the closing minutes of Game 6.[34] When asked about a rivalry with the Los Angeles Lakers, Clippers center DeAndre Jordan stated, "I don't think it'll ever be a rivalry. You guys [in the media] want it to be, though. I would say Memphis more than the Lakers. I hate every other NBA team in the league. If anybody [is our rival], I'd say Memphis."[35] Although the two teams never met in the 2014 playoffs, they still engaged in close, heated matchups in the 2014–15 season. In a Grizzlies home game against the Clippers, the crowd was given flip-flop sandals designating Clippers players as "floppers".

The Grizzlies also have a rivalry brewing with the Oklahoma City Thunder. The two squads have faced each other in the playoffs in 2011, 2013, and 2014. The Thunder beat the Grizzlies in the conference semifinals in 2011 and in the conference quarterfinals in 2014. Each of those two series went to seven games. The Grizzlies handled the Thunder in five games during the conference semifinals in 2013 before getting beat by the San Antonio Spurs in the conference finals that same year.

^Coon, Larry. "NBA Salary Cap FAQ – 2011 Collective Bargaining Agreement". Retrieved April 13, 2014. If the player is already under contract to, or signs a contract with a non-NBA team, the team retains the player's draft rights for one year after the player's obligation to the non-NBA team ends. Essentially, the clock stops as long as the player plays pro ball outside the NBA.